Accelerated Adaptation of SARS-CoV-2 Variants in Mice Lacking IFITM3 Preserves Distinct Tropism and Pathogenesis
Abstract:
Here we investigated whether interferon induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. Enhancements associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enabled comparative studies of variants in mice. Beta caused lung dysfunction and altered cilia-associated gene programs, consistent with broad viral antigen distribution in lungs. Omicron, which shows low pathogenicity and upper respiratory tract preference in humans, replicated to high nasal titers while showing restrained spatial distribution in lungs and diminished lung inflammatory responses compared to Beta. Our findings demonstrate that IFITM3 deficiency accelerates coronavirus adaptation and reveal that intrinsic SARS-CoV-2 variant traits shape tropism, immunity, and pathogenesis across hosts.
Highlights:
IFITM3 is a critical barrier to SARS-CoV-2 adaptation in new host speciesMouse-adapted SARS-CoV-2 strains enable comparative pathologyOmicron favors nose and large airways, leading to mild lung pathologyBeta exhibits broad lung replication, driving severe inflammation and dysfunction.
Insights
Interferon-induced transmembrane protein 3 (IFITM3) deficiency accelerates SARS-CoV-2 adaptation in new hosts. This study reveals how IFITM3 influences viral evolution and pathogenesis, impacting interspecies transmission.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Interferon-induced transmembrane protein 3 (IFITM3) is a crucial antiviral protein.
- Certain human populations have deficiencies in IFITM3.
- Understanding IFITM3's role in SARS-CoV-2 interspecies adaptation is critical.
Purpose of the Study:
- To investigate the effect of IFITM3 deficiency on SARS-CoV-2 interspecies adaptation.
- To analyze the impact of IFITM3 on viral replication, pathogenesis, and mutation accumulation.
- To compare the tropism and immune responses of different SARS-CoV-2 variants in IFITM3-deficient hosts.
Main Methods:
- Passaging SARS-CoV-2 variants (Beta and Omicron) through IFITM3-deficient and wild-type mice.
- Analyzing viral replication, pathogenesis, and amino acid substitutions in the viral genome.
- Comparative pathological and immunological studies of mouse-adapted SARS-CoV-2 strains.
Main Results:
- IFITM3 deficiency enhanced SARS-CoV-2 Beta and Omicron variant replication and pathogenesis in mice.
- Amino acid substitutions in the viral genome were associated with IFITM3 deficiency, suggesting limited adaptive mutation accumulation.
- Omicron showed high nasal titers with limited lung distribution and inflammation, while Beta caused severe lung dysfunction and inflammation.
Conclusions:
- IFITM3 acts as a significant barrier to SARS-CoV-2 adaptation in new host species.
- Mouse-adapted SARS-CoV-2 strains facilitate comparative pathology studies.
- SARS-CoV-2 variant-specific traits dictate tropism, immunity, and pathogenesis across hosts.
